Ophthalmic oil-in-water emulsions containing prostaglandins

Abstract

The present invention refers to an oil-in-water emulsion for ophthalmic application comprising at least one prostaglandin as active agent and a surfactant component comprising a combination of at least two non-ionic surfactants. The emulsion is suitable for medical applications, particularly for the treatment of glaucoma, and has an increased chemical stability of the prostaglandin active agent so to allow long-term storage also at room temperature.

1 . An oil-in-water emulsion having a substantially neutral zeta potential for ophthalmic use comprising as components
 (i) a dispersed oily phase,   (ii) at least one prostaglandin as active agent, which is dissolved in the oily phase component (i),   (iii) a surfactant comprising a combination of at least two non-ionic surfactants, and   (iv) a contiguous aqueous phase, optionally comprising formulation agents.   
     
     
         2 . The oil-in-water emulsion of  claim 1 , wherein the oily phase (i) is present in an amount of at least 5% (w/w) based on the total weight of the emulsion. 
     
     
         3 . The oil-in-water emulsion of  claim 1 , wherein the oily phase component (i) is selected from pharmaceutically acceptable oils, such as animal or vegetable oils, synthetic oils and mixtures thereof. 
     
     
         4 . The oil-in-water emulsion of  claim 1 , wherein the oily phase component (i) is selected from the group consisting of ethyl oleate, a mixture of C 8  to Cio fatty acid triglycerides, ricinus oil, corn oil or mixtures thereof. 
     
     
         5 . The oil-in-water emulsion of  claim 1 , wherein the oily phase (i) has a solubilization degree of at least 0.1 mg/ml for the prostaglandin component (ii). 
     
     
         6 . The oil-in-water emulsion of  claim 5 , wherein the oily phase (i) has a solubilization degree of at least 10 mg/ml for the prostaglandin component (ii). 
     
     
         7 . The oil-in-water emulsion of  claim 1 , wherein the oil/water partition coefficient of the prostaglandin component (ii) is at least log P=0.5 in favor of the oily phase (i). 
     
     
         8 . The oil-in-water emulsion of  claim 7 , wherein the oil/water partition coefficient of the prostaglandin component (ii) is at least log P=2 in favor of the oily phase (i). 
     
     
         9 . The oil-in-water emulsion of  claim 1 , wherein the prostaglandin component (ii) is a prostaglandin F1α analogue. 
     
     
         10 . The oil-in-water emulsion of  claim 9 , wherein the prostaglandin component (ii) is selected from the group consisting of latanoprost, travoprost, bimatoprost and unoprostone and mixtures of two or more thereof. 
     
     
         11 . The oil-in-water emulsion of  claim 10 , wherein the prostaglandin component (ii) is latanoprost. 
     
     
         12 . The oil-in-water emulsion of  claim 1 , wherein the at least two non-ionic surfactants of the surfactant component (iii) are selected from lipophilic non-ionic surfactants, hydrophilic non-ionic surfactants or combinations thereof. 
     
     
         13 . The oil-in-water emulsion of  claim 1 , wherein the non-ionic surfactants of the surfactant component (iii) have a combined total HLB value of at least 10, preferably of at least 13 and preferably up to 18. 
     
     
         14 . The oil-in-water emulsion of  claim 1 , wherein the at least two surfactants of the surfactant component (iii) are present in a self-emulgation promoting amount. 
     
     
         15 . The oil-in-water emulsion of  claim 1 , wherein the non-ionic surfactants of the surfactant component (iii) are selected from the group consisting of polyoxyethylene (20) sorbitan monooleate (Tween 80®), polyoxyethylene (20) sorbitan monolaurate (Tween 20®), polyoxyethylene (2) cetylether (Brij 52®), polyoxyetylene (10) cetylether (Brij 56®), polyoxyethylene (20) cetylether (Brij 58®). 
     
     
         16 . The oil-in-water emulsion of  claim 15 , wherein the combination of non-ionic surfactants of the surfactant component (iii) is selected from the combinations polyoxyethylene (20) sorbitan monooleate (Tween 80®)/polyoxyethylene (20) sorbitan monolaurate (Tween 20®), polyoxyethylene (20) sorbitan monooleate (Tween 80®)/polyoxyl (2) cetylether (Brij 52®), polyoxyl (2) cethylether (Brij 52®)/polyoxyl (20) cethylether (Brij 58®) and polyoxyl (20) cethylether (Brij 58®) polyoxyl (10) cethylether (Brij 56®). 
     
     
         17 . The oil-in-water emulsion of  claim 1 , wherein the aqueous phase component (iv) is a pharmaceutically acceptable aqueous phase, preferably selected from the group consisting of sterilized water, purified water or of any other type of water suitable for ophthalmic application. 
     
     
         18 . The oil-in-water emulsion of  claim 1 , wherein the aqueous phase component (iv) optionally comprises further additives such as buffer agents, isotonic agents, viscosity-increasing compounds, antimicrobial preservatives, antioxidants, stabilizers. 
     
     
         19 . The oil-in-water emulsion of  claim 18 , wherein the antimicrobial preservative is chlorobutanol. 
     
     
         20 . The oil-in-water emulsion of  claim 1 , which has a zeta potential between −10 mV and +10 mV, preferably between −4 mV and +4 mV. 
     
     
         21 . The oil-in-water emulsion of  claim 1 , which is a microemulsion wherein the average size of the oil droplets is less than 1 μm. 
     
     
         22 . The oil-in-water emulsion of  claim 1 , wherein the average droplet size of the oily droplets of the emulsion is 700 nm or less. 
     
     
         23 . The oil-in-water emulsion of  claim 1 , which has a stability of at least 6 months, preferably at least 9 months, more preferably at least 12 months at 25° C. 
     
     
         24 . The oil-in-water emulsion of  claim 1 , wherein the components (i) to (iv) are present in the following amounts: (i) 5.0-20.0% (w/w) of the oily phase, (ii) 0.001-5.0% (w/w) of the prostaglandin active agent, (iii) 0.1-10.0% (w/w) of the first non-ionic surfactant and 0.1-10.0% (w/w) of the second non-ionic surfactant, and (iv) 50.0-95.0% (w/w) of the aqueous phase; based on the total weight of the emulsion. 
     
     
         25 . The oil-in-water emulsion of  claim 1  characterized in that the emulsion is free from cosurfactant components, in particularly selected from short chain alcohols, mono carboxylic acids, cationic and/or anionic surfactants, lecithins and/or phospholipids. 
     
     
         26 . The oil-in-water emulsion of  claim 1  for use as an ophthalmic formulation for the prevention, alleviation and/or treatment of glaucoma and/or ocular hypertension. 
     
     
         27 . A process for the preparation of the oil-in-water emulsion of  claim 1 , comprising the steps
 (a) optionally solubilising formulation agents in the aqueous phase,   (b) solubilising the first non-ionic surfactant either in the aqueous or oily phase,   (c) solubilising the second non-ionic surfactant either in the aqueous or oily phase,   (d) solubilising the prostaglandin active agent in the oily phase, and   (e) mixing the oily phase with the aqueous phase.   
     
     
         28 . The process of  claim 27 , wherein the mixing step (e) is performed without the use of high energy shear processes such as high pressure homogenisation or sonication. 
     
     
         29 . The process of  claim 27 , wherein an oil-in-water emulsion is spontaneously formed in the mixing step (e). 
     
     
         30 . The process of  claim 27 , wherein the mixing step (e) is performed with the use of high energy shear processes such as high pressure homogenisation or sonication.